With the improvement of people's living standards, obesity resulting from unreasonable diet becomes more and more acutely in daily life. Experts from the Obesity Society are recognizing obesity as a global obesity epidemic, and its rate is rising increasingly. According to a document of the WHO, 1 billion people are overweight and at least 300 million people are obese. Obesity happens not only in the developed countries, but also in the developing countries. In the 11th European congress on obesity, China has been included into the Ranking of Obesity Rate for the first time. Obesity, as well as AIDS, drug and alcohol addiction are considered four dangerous social problems for human health in the world. It may provocate or aggravate the incidence of some common chronic diseases, especially diabetes, cardiovascular system diseases, and sleep apnea syndrome. Statistics show that in the past 10-20 years 280,000-325,000 people die per year because of obesity or its complications. Although the development of a sense of self-care people can use many ways to control weight, such as regular exercise in accompany with reasonable diet, few have long-term beneficial effects. Therefore a weight-reducing drug is increasingly desired, and thus developing safe and effective weight-loss drugs will bring extraordinary social and economic returns.
Sibutramine hydrochloride, 1-(4-chlorophenyl)-N,N-dimethyl-α-(2-methylpropyl)cyclobutanemethanamine hydrochloride monohydrate, is a weight-loss drug developed by Konll Company (BASF, Germany), and is a serotonin-noradrenalin reuptake inhibitor. In November 1997, Sibutramine hydrochloride was given approval as weight-loss drug by F.D.A. and then went on market in February 1998 with brand name of Meridia. In the same year 1998, sales amount of Meridia was 194 million US dollars, and rose to more than 300 million US dollars in 1999. Meridia has been one of the mainstream products over European and US weight-loss market and sold well in nearly 20 countries. Meridia has been one of the four main products of BASF. In May 2000, this product received the approval by SDA in China with brand name of QuMei. Until now, there are nearly 3 million people taking Sibutramine hydrochloride over the world.
Sibutramine HCl is a serotonin-noradrenalin reuptake inhibitor (Buckett, W. R., Thomas, P. C., Luscombe, G. P., Prog. Neuropsychopharmacol. Biol. Psychiat, 1988, 12: 575-584; Luscombe, G. P., Hoperoft, R. H., Thomas, P. C., Buckett, W. R., Neuropharmacology, 1989, 28: 129-134). It is confirmed that Sibutramine Hydrochloride can reduce weight by a two-way effect. On one hand, it can increase satiety to decrease food consumption (Fantino, M., Souquet, A.-M., Int. J. Obesity, 1995, 19: 145; Halford, J. C. G, Heal, D. J., Blundell, J. E., Brit. J. Pharmacol 1995, 114: 387P; Stricker-Krongrad, A., Souquet, A.-M., Burlet, C., Int. J. Obesity, 1995, 19: 145). On the other hand, it can stimulate heat production to enhance energy consumption (Connoley, I. P., Heal, D. J., Stocl, M. J., Brit. J. Pharmacol, 1995, 114: 388P; Connoley, I. P., Frost, I., Heal, D. J., Stocl, M. J., Brit. J. Pharmacol, 1996, 117: 170P). Additionally, Sibutramine hydrochloride can decrease waist-hip ratio, and at the same time reduce the concentration of triglyceride, total cholesterol, and LDL-ch in blood, and increase the concentration of HDL-ch in blood (Qifu Lee, et al., Chinese Journal of Endocrinology and Metabolism, 2002, 18(3): 204-205; Jian Wu, et al., Medical Journal of Chinese People's Liberation Army, 2002, 27(2):172-176; Jian Wu, et al., Chinese Journal of Endocrinology and Metabolism, 2001, 18(3): 201-202).
It has been revealed that Sibutramine HCl can reduce 5%-10% basal weight and retain weight loss very well. Sibutramine hydrochloride did not show obviously sedative, stimulant or adrenergic effects, and had good drug tolerance. However, dry mouth, headache, anorexia, constipation and insomnia would be the side effects.
It has been further revealed that Sibutramine HCl and its demethylated derivative can treat nervous and mental diseases such as obesity, insomnia, tiredness, depression and the like; metabolic diseases; and cardiovascular diseases. For Sibutramine HCl, its stereoisomers and its demethylated derivative, PCT/US2000/007202 has disclosed that they can decrease the weight gain after pregnancy; PCT/US2000/007255 has disclosed that they can reduce platelet adhesion; PCT/US2000/007122 has disclosed their treatment on chronic fatigue syndrome; PCT/US2000/007123 has disclosed their treatment on metabolic syndrome; PCT/US2000/007361 has disclosed their effect on obesity related tumor; PCT/US2000/007124 has disclosed their treatment on pulmonary hypertension; PCT/US2000/007177 has disclosed their treatment on sleep syndrome; PCT/US2000/001217 has disclosed their action on smoking cessation; U.S. Pat. No. 6,046,242 has disclosed their treatment on urinary incontinence. It has been provided many methods to resolve the enantiomers of Sibutramine HCl in large scale (Tetra Asymm 2003, 14(25): 3553-3556).
In addition, researchers in the chemical synthesis field have also provided many methods of modifying Sibutramine HCl, such as routes of asymmetric synthesis of R-sibutramine (Organic process research and development 2006, 10(2): 327-333); demethylation methods of sibutramine (U.S. Pat. No. 6,399,826); asymmetric synthesis of demethylated R-sibutramine (Tetra Lett, 2002, 43(13): 2331-2333). Researches on individual modification of methyl, amino and cyclobutyl of demethylated sibutramine and preparation of pure optical isomer of above derivatives were also provided (J. Chem. Soc. Perkin Trans. 1; EN; 21; 1996; 2583-2590). In the literature, Org. Lett. 2005: 2599-2602, methyl and amino of demethylated sibutramine were modified, and optical isomer of this derivative was resolved.
However, above researches only relate to the chemical moiety of the sibutramine modified derivatives. There is no literature that relates to the acidification of the amino of double-demethylated sibutramine derivatives. Further, there is no literature focusing on deep research on weight loss effect of sibutramine derivatives or comparison between their enantiomers.